User:Benjah-bmm27/degree/3/APD

Asymmetric synthesis, APD

Chirality

• Can have chiral centres at many different atoms:
  • C: sp³ carbon with four different substituents
  • N: ammonium ion with four different substituents on nitrogen
  • P: phosphines with three different substituents on phosphorus (P lone pair is configurationally stable)
  • S: sulfoxides with two different substituents on sulfur (S lone pair is also configurationally stable)
• Can also have axial chirality, as seen in certain allenes, 1-ethylidene-4-methylcyclohexane, BINAP, and various other molecules

Asymmetric synthesis

• Asymmetric synthesis
• Natural molecules are chiral and enantiopure, so enantiomers have different biological effects
  • Limonene's R enantiomer smells of orange, whereas the S enantiomer smells of lemon
  • Aspartame is very sweet, but its enantiomer and all its diastereomers are bitter

• Enantiopure drugs are now standard
  • Only the R enantiomer of prozac is effective as an antidepressant
  • The S enantiomer of propranolol is a beta-blocker, whereas the R enantiomer has recently been discovered to act as a contraceptive (although not used as such)
  • Thalidomide has a useful R enantiomer, whereas the S enantiomer is a teratogen - but racemises in vivo so enantiopurity is no solution

• Unsymmetrical ketones (e.g. acetophenone) have Re and Si enantiotopic faces, so reduction with NaBH₄ leads to a racemic mixture of S and R alcohols, respectively (due to enantiomeric transition states, which must have equal energy)
  • Can make one enantiomer at a greater rate but using a chiral analogue of BH₄⁻ (transition states now diastereomeric, thus not equal in energy)
  • Often an unsuitable solution, as the chiral reagent can be large and expensive, and possibly only slightly enantioselective

Enantiomeric excess

• Simplest measure of enantiopurity is enantiomeric ratio (e.r.): the ratio of major to minor enantiomers.
• However, almost universally used in enantiomeric excess (e.e.): the percentage of one enantiomer minus the percentage of the other
  • If the e.r. is 9:1, the e.e. is 90% − 10% = 80%
  • if the e.r. is 99:1, the e.e. is 99% − 1% = 98%
• Analogously, mixtures of diastereomers are characterised by diastereomeric ratio (d.r.) and diastereomeric excess (d.e.)

• Can determine e.e. by derivatisation
• A chiral derivatizing agent converts enantiomers to diastereomers, which have different physical properties
• The diastereomeric derivatives can then be separated by HPLC or GC, or quantified by integration of ¹H or ¹⁹F NMR spectra
• Mosher's acid chloride is a common, but expensive, derivatising reagent for NMR - makes Mosher esters from alcohols
  • Its chiral carbon is quaternary, so cannot epimerise
  • Its methoxy group gives a singlet in ¹H, while its trifluoromethyl group gives a singlet in ¹⁹F NMR
  • Can get misleading results if derivatisation reaction goes faster for one enantiomer
• Can also use chiral NMR shift reagents, which form hydrogen bonds with analyte molecules, generating diastereomeric complexes
• Chiral stationary phases for chromatography are available
  • Cyclic starch (based on a cyclodextrin) for chiral GC
  • Cellulose or starch with free OH groups converted to aryl carbamates, for chiral HPLC

Resolution of enantiomers

• Chiral resolution
• From a racemic mixture, convert the enantiomers to diastereomers, separate them, then discard the unwanted diastereomer
• Simple but wasteful, 50% of the racemic product is discarded
• Commonly convert to diastereomers with a mandelic acid derivative, (R)-2-methoxy-2-phenylacetyl chloride
• Crystallization is the most convenient resolution method
  • Can often form enantiopure crystals by salt formation with a chiral acid or base
  • In the synthesis of indinavir, the racemic product of a Ritter reaction is hydrolysed to an amino alcohol, then reacted with tartaric acid
  • One enantiomer forms a crystalline tartrate salt, whereas the other one is soluble
  • Separate by filtration, then regenerate enantiopure amino alcohol from its tartrate with NaOH
  • Benefit is simplicity - widely used industrially
  • Many enantiopure acids and bases available from nature:
    • Tartaric acid
    • Camphorsulfonic acid
    • (−)-Cinchonidine
    • (−)-Quinine
    • Brucine (very toxic!)
    • α-Methylbenzylamine

Chiral pool

• Dipping into the chiral pool means starting from an enantiopure chiral compound from nature
  • Effective but may involve many steps

Chiral auxiliaries

• Chiral auxiliary – a chiral molecule temporarily added to a substrate. With the auxiliary attached, the substrate undergoes a diastereoselective reaction to form mostly one of two possible diastereomers. Subsequent removal of the auxiliary leaves enantiomeric products, hopefully with one enantiomer in great excess.
• Evans' chiral auxiliary
  • Control conformation of Evans-derivatized substrate in Diels-Alder reaction with Et₂AlCl, forming a chelate with the two carbonyl groups
• 8-Phenylmenthol
  • Used by Corey in enantioselective prostaglandin synthesis
  • Synthesised from the (S) enantiomer of the natural product pulegone
  • Its OH group reacts with acyl chlorides to form 8-phenylmenthyl esters
  • 8-Phenylmenthyl acrylate esters can undergo asymmetric Diels-Alder reactions with achiral cyclopentadienes in the initial stages of the syntheses of several prostaglandins

Chiral reagents and catalysts

Asymmetric reduction

Asymmetric reduction of ketones

• Alpine borane from α-pinene and 9-BBN
• Ipc₂BCl
• CBS reduction, first asymmetric catalytic reduction
  • Corey's oxazaborolidine catalyst synthesised from proline

Homogeneous catalytic hydrogenation of ketones and alkenes

• Noyori asymmetric hydrogenation of ketones — R. Noyori (Nobel Prize 2001)
  • Method for functionalised ketones uses 0.01-1 mol% square planar BINAP-RuX₂ (usually, X = Cl or Br) and 40-100 atm H₂
  • Method for simple ketones uses 0.01 mol% octahedral trans-S-XylBINAP-S-daipen-RuCl₂, 10 atm H₂, tBuOK, iPrOH (daipen is a diamine ligand)

• Asymmetric catalytic hydrogenation of alkenes for the synthesis of L-DOPA at Monsanto — W. S. Knowles (Nobel Prize 2001)

Asymmetric oxidation

• Asymmetric oxidation — K. B. Sharpless (Nobel Prize 2001)
• The Nobel Prize in Chemistry 2001
  • Press release
  • Summary for the public
  • Advanced information
  • Further reading

Sharpless asymmetric dihydroxylation

• Sharpless asymmetric dihydroxylation

Sharpless epoxidation

• Sharpless epoxidation
  • tert-butyl hydroperoxide, tBuOOH
  • titanium isopropoxide, Ti(OiPr)₄
  • diethyl tartrate, (+)-DET
  • molecular sieve catalyst

Jacobsen epoxidation

• Jacobsen epoxidation
  • Jacobsen's catalyst is synthesised from trans-1,2-diaminocyclohexane (either the S,S or R,R enantiomer) and 3,5-di-tert-butyl-2-hydroxybenzaldehyde (which together form a salen-type ligand), manganese(II) acetate and lithium chloride in the presence of air
  • Jacobsen's catalyst is oxidised from Mn(III) to Mn(IV) by sodium hypochlorite: L₂(RO)₂Mn-Cl + NaOCl → L₂(RO)₂Mn=O
  • Oxidised catalyst converts cis-alkenes to their epoxides
  • Example: cis-β-methylstyrene is converted to (2R,3S)-2-methyl-3-phenyloxirane with (S,S)-Jacobsen's catalyst
  • (R,R)-Jacobsen's catalyst gives the (2S,3R) epoxide

Miscellaneous

• Asymmetric reduction
  • Alpine borane from α-pinene and 9-BBN
  • Ipc₂BCl
  • Asymmetric catalytic reduction
    • Asymmetric catalytic hydrogenation for the synthesis of L-DOPA at Monsanto — W. S. Knowles (Nobel Prize 2001)
    • Noyori asymmetric hydrogenation — R. Noyori (Nobel Prize 2001)
• Asymmetric oxidation — K. B. Sharpless (Nobel Prize 2001)
  • • Sharpless oxyamination
    • Sharpless asymmetric dihydroxylation
    • Sharpless epoxidation
      • tert-butyl hydroperoxide, tBuOOH
      • titanium isopropoxide, Ti(OiPr)₄
      • diethyl tartrate, (+)-DET
      • molecular sieve catalyst
• The Nobel Prize in Chemistry 2001
  • Press release
  • Summary for the public
  • Advanced information
  • Further reading

• Jacobsen epoxidation
• Oxaziridines

Enzymatic transformations

• Enzymes are highly efficient chiral catalysts that generate enantiopure products. However...
  • Enzymes have evolved to use substrates found in biological systems, so won't operate on most organic molecules
  • Enzymes often require stoichiometric reagents (co-factors) such as NADH
  • Enzymes have evolved in aqueous biological systems, often limiting us to using them in water (but lipases work well in nonpolar solvents)
  • These problems can often be overcome, so certain enzymes are very useful for certain transformations in asymmetric synthesis

Dehydrogenases

• Dehydrogenases need a cofactor, so just use the whole organism: yeast
  • Converts ketones to secondary alcohols

Lactate dehydrogenase

• Lactate dehydrogenase works best isolated, so need to supply your own catalytic NADH and regenerate it with sacrificial isopropanol:
  • α-keto acid + NADH --[lactate dehydrogenase]--> α-hydroxy acid + NAD⁺
  • NAD⁺ + isopropanol --[dehydrogenase]--> NADH + acetone
• Example: achiral pyruvic acid → chiral (S)-lactic acid

Hydrolases

• Hydrolases catalyse reactions with water, so don't need a cofactor
• Common hydrolases
  • Pig liver esterase (PLE)
  • Aspergillus niger epoxide hydrolase (AnEH)
• Great for kinetic resolution, but as with any resolution method, usually limited to 50% yield
• However, with meso-substrates, get up to 100% yield by internal kinetic resolution
• Asymmetric ester hydrolysis with pig liver esterase
  • PLE enantiospecifically hydrolyses one of the two methyl ester groups in a meso compound, which one depends on the size of the ring

Lipases

• Esterases that act on lipids are termed lipases
• Lipases work well in nonpolar solvents
• Can use lipases to effect transesterification, acetylating an alcohol with vinyl acetate, a high energy acyl donor
• Candida lipase with vinyl acetate will enantiospecifically acetylate one of the two OH groups in the meso compound cis-4-cyclopentene-1,3-diol (CAS # 29783-26-4)
• The other enantiomer of the product can be made by acetylating both OH groups with acetic anhydride, then enantiospecifically hydrolysing one of them with Candida lipase and water